The three major forms of male sexual dysfunction are premature ejaculation (PE), erectile dysfunction (ED), and decreased libido. The American Urological Association defines premature ejaculation as ejaculation that occurs sooner than desired, either before or shortly after penetration, causing distress to either one or both partners (Guideline on the Pharmacologic Management of Premature Ejaculation, American Urological Association, 2004). The dysfunction is classified as either lifelong (primary) or acquired (secondary). Premature ejaculation is among the most prevalent of male sexual complaints. A survey has estimated that PE affects approximately 25% to 30% (about one in five to about one in three) of men of all ages (see, Laumann et al., JAMA, 281: 537-544 (1999)). In the United States, approximately 25 million men between the ages of 18 and 59 experience PE. Whatever the actual figures, persistent PE can leave sexual partners feeling unsatisfied or unfulfilled, can cause stress or embarrassment to the affected male individual, and can lead to a deterioration of the intimate relationship between partners.
Treatments for PE include psychotherapeutic/behavioral therapies and pharmacological treatments (for a review, see, Sharlip, J. Sex Med., Supp. 2: 103-109 (2005)). Among the pharmacological agents reported to provide some desirable delay in ejaculation in the male patient are topical anesthetics, non-selective serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), and phosphodiesterase-5 inhibitors (PDE-5). Topical anesthetics, e.g., preparations containing benzocaine or a lidocaine-prilocaine combination, are applied to the penis to diminish sensitivity and delay ejaculation. However, topically applied anesthetics can cause irritation to either or both partners or result in an undesired hypoesthesia that prevents orgasm.
Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs used to treat depression and various anxiety or personality disorders. SSRIs have also been reported to delay or inhibit sexual climax and to delay ejaculation. Such sexual side effects, including delay of ejaculation, have been reported for such well known antidepressants as fluoxetine (commercially available as PROZAC®, Eli Lilly and Company, Indianapolis, Ind.), sertraline (commercially available as PAXIL®, GlaxoSmithKIine plc, London, United Kingdom), paroxentine (commercially available as ZOLOFT®, Pfizer Inc., New York, N.Y.), and dapoxetine (Alza Corporation, Mountain View, Calif.). Accordingly, SSRIs have also been the focus for developing treatments for PE. Similar sexual side effects have been noted in patients treated with the tricyclic antidepressant clomipramine (e.g., ANAFRANIL®, Novartis International AG, Basel, Switzerland), which has also been used to treat PE.
Use of most antidepressants, such as currently employed SRIs or SSRIs, to treat PE has typically been proposed to involve a chronic continuous dosing regimen analogous to those employed in treating depression or severe personality disorders. However, chronic dosing regimens for SRIs and SSRIs increase the risk of accumulating one or more side effects, including undesired anti-cholinergic effects, reduced sexual desire, genital anesthesia, headache, nausea, sweating, and dizziness. The risk or emergence of such side effects is justified in view of the benefit for treating chronic depression, abnormal anxiety, or severe personality disorders. In cases in which dosing of an SSRI has been used to treat PE on an acute or “as needed” (pm) basis, the efficacy of the drug has been undesirably diminished. With chronic continuous dosing, even when administered at doses below those normally used to treat depression, psychoactive drugs such as SSRIs may eventually cause one or more adverse side effects that contra-indicate their continued use or that ultimately diminish compliance by patients who do not require treatment for debilitating depression or severe personality disorders.
Dapoxetine is the first SSRI drug that was specifically developed to treat PE. The pharmacokinetics of dapoxetine, e.g., faster acting and faster clearance than other SSRIs, were seen as particularly desirable for the development of an orally administrable dapoxetine tablet that could be taken one to three hours before sexual activity, thereby providing an “on demand” or “as needed” (pm) treatment that eliminated the need for the chronic continuous dosing employed for off-label uses of other SSRI antidepressants. Side effects are similar to those found with other SSRI drugs with nausea, diarrhea, and dizziness being among the most prevalent in clinical trials. In October 2005, the United States Food and Drug Administration issued a not-approvable letter for a new drug application for dapoxetine treatment of PE.
Clearly, needs remain for more effective pharmacologic treatments for PE.